Craniofacial abnormalies in humans and the other organisms are common birth defects, although few are heritable conditions. Most research on basic body and facial structural development is interpreted from lower organisms, such as Drosophilia and zebrafish. Unlike the mouse, cats are strongly selected for facial structures. Felines are more related evolutionarily to humans than to mice, with similar genomic organization. Thus, transferring basic and clinical research on the processes that affect normal and abnormal development of craniofacial structures in the cat to humans will be extremely efficient. The long-term goal of this research is to understand the genetic components of craniofacial development in humans. The primary goal is to develop the feline into a model for human facial development. Burmese cats have a single gene defect that causes duplication of the upper maxillary region of the face. The interactions of mutations and genes for feline facial development will be more similar to humans than other current animal models. Three approaches will be used to develop the model. Specific Aim 1: Isolate feline homologs of developmental genes and gene-associated microsatellites from the cat BAC library. Genes in the HOX clusters and Sonic Hedgehog have been shown to strongly influence facial development. The hypothesis is that one of these genes causes the feline facial defect. Highly polymorphic microsatellite markers that are in juxtaposition to the genes will also be isolated from the cat. Specific Aim 2: Scan Sonic Hedgehog for causative mutations. Sonic hedgehog has a strong influence on the upper maxillary region. Specific Aim 3: Linkage analysis in feline pedigrees. Gene-associated markers will be analyzed in previously collected feline families that segregate for the cranial facial defect. This approach will support the candidate gene efforts. The hypothesis is that a linkage analysis will identify the chromosomal region for the candidate gene, focusing the search for the candidate gene. Once identified, mutation analyses of these genes in the cat or other species will lead to understanding the genetics of facial development in humans. [unreadable] [unreadable]